This revised application for our new Program Project Grant brings together a group of investigators who are experts in the areas of molecular and cellular immunology and human and mouse genetics. We propose to study the role of single genes in the pathogenesis of X-linked Lymphoproliferative syndrome (XLP), Common variable immunodeficiency (CVID), Omenn syndrome and Severe Combined Immunodeficiencies (SCID) in an application, entitled: "Primary Immunodeficiencies Affecting Specific Stages of the Adaptive Immune Response" Because of successful preliminary analyses of patient materials, exciting findings in genetically altered mice, this application seeks to define how mutations in the SH2D1A, SH2D1B/C, TACI, RAG-1/2, DNA Ligase IV or Cernunnos genes affect T and B cell development and T cell dependent and/or T cell-independent immunoglobulin responses. We will use our recently acquired insights into the causes of these diseases in the following four interlinked projects and an Administrative Core: Project #1 Role of the SAP (SH2D1A) gene in T cell-dependent antibody responses. Cox Terhorst, Beth Israel Deaconess Medical Center. Project #2 Role of in TACI mutations in Common Variable Immunodeficiency Raif Geha, Children's Hospital of Boston. Project #3 Gene knock-in models for Omenn syndrome and leaky SCID. Luigi Notarangelo, Children's Hospital of Boston. Project #4 Mouse Models of Severe Combined Immunodeficiencies. Fred Alt, Children's Hospital of Boston. Core A Administrative Core Cox Terhorst, Beth Israel Deaconess Medical Center. The outcomes of proposed studies should lead to better understanding of the complex and often alternate disease manifestations that are caused by mutations in a single gene. The results of these studies should suggest therapeutic strategies that can be applied to these PID patients and may unravel molecular and cellular mechanisms that are generally involved in immune dysregulation, autoimmunity and cancer.